Burden of chronic kidney disease in Nepal: An analysis of the burden of disease from 1990 to 2019

Chronic kidney disease (CKD) has emerged as one of the major public health concerns. The increasing prevalence of its correlates such as obesity, diabetes, and hypertension has been, due in part responsible for the increased burden. However, very few studies have presented the comprehensive data on burden of disease particularly in developing countries like Nepal. In this study, we have performed an analysis on prevalence, mortality, years lived with disability (YLDs), years of life lost (YLLs) and disability-adjusted life years (DALYs) attributable to CKD in Nepal using Global Burden of Disease (GBD) Study 2019. The GBD 2019 study provides estimation of the prevalence, mortality rates, YLDs, YLLs and DALYs due to 369 different disease and 87 risk factors for 204 countries and territories across the world. In this study, we present Nepal specific data on prevalence, mortality, YLDs, YLLs and DALYs related to CKD. In 2019, there were 1,895,080 prevalent cases of CKD with 5,108 deaths, and a total of 168,900 DALYs were attributable to CKD. Age-standardized prevalence rate of CKD increased from 5,979.1 cases per 100,000 population (95% UI: 5539.7, 6400.4) in 1990 to 7,634.1 cases per 100,000 population (95% UI: 7138.8, 8119.4) in 2019 with higher prevalence in males. Similarly, the age-standardized mortality due to CKD increased for both sexes from 0.8 deaths per 100,000 population (95% UI: 0.6, 1.0) in 1990 to 2.6 deaths per 100,000 population (95% UI: 2.0, 3.3) in 2019. The burden of CKD as a percentage of total DALYs was 0.5% (95% UI: 0.4, 0.6) in 1990 and increased to 1.8% (95% UI: 1.4, 2.2%) in 2019. Kidney dysfunction, high systolic blood pressure, high fasting plasma glucose, high body mass index, low temperature, lead exposure, diet high in sodium, and high temperature were found to be the major risk factors for CKD. The study reveals that Nepal has a high and rising burden of CKD. Innovative strategies for prevention of CKD including health system preparedness for treatment services are required to respond to the rising burden of CKD.


Introduction
Chronic kidney disease (CKD) is recognized as a public health concern [1]. In general, CKD has been defined as "sustained damage of renal parenchyma that leads to chronic deterioration of renal function and may gradually progress to end-stage renal disease" [2]. However, technically, CKD has been defined as a condition for a minimum of 3 months which is marked by glomerular filtration rate (GFR) below 60 mL/min per 1.73 m2 and/or when ratio of albumin to creatinine in urine is above 30 mg/g irrespective of any underlying cause [3,4].
Studies suggest that, from high to low income countries, hypertension and diabetes mellitus (DM) are two major causes of CKD [4,7]. Other cause include high cholesterol, glomerulonephritis, kidney infections, polycystic kidney disease, blockages in the urinary tract, cardiovascular diseases (CVDs) and use of certain drugs such as non-steroidal anti-inflammatory drugs [7,8]. Few studies on the burden attributable to specific illness and even fewer studies on the burden of CKD are conducted in low and middle-income countries like Nepal [9]. Although few previous studies have reported the prevalence of CKD in Nepal [10,11], the data on mortality attributable to CKD and complete picture of the burden of disease are not available. In this context, we have performed an analysis on prevalence, mortality, YLDs, YLLs and DALYs attributable to CKD in Nepal using Global Burden of Disease (GBD) Study 2019.

Methods
We obtained data from GBD study 2019, coordinated by the Institute for Health Metrics and Evaluation (IHME) for this analysis. The GBD 2019 is a systematic analysis that aims to estimate the burden of 369 diseases and 87 risk factors across 204 countries and territories. The study provides the estimates for mortality rates, YLDs, YLLs, and DALYs associated with different disease and risk factors. From GBD 2019 study, we have extracted Nepal-specific data for CKD prevalence, YLLs, YLDs, DALYs, and mortality [5].
The GBD study uses data sources such as the census, civil registration and vital statistics, disease registries, household surveys, health service utilization, air pollution monitors, disease notification, among others. The study views CKD as both a metabolic risk factor and a disease. For the purposes of this study, CKD is defined as having an estimated GFR of less than 60 mL/ min per 1.73 m 2 [12].
The 2019 edition of the GDB study attributed each death to a single underlying cause using the international classification of diseases and then classified it into a four-level mutually exclusive and collectively exhaustive GBD cause list. The list includes communicable, maternal, neonatal, and nutritional disorders (CMNN diseases), non-communicable diseases (NCDs), and injuries at level 1, while level 2 consists of 22 clusters of disease and injury aggregates. Meanwhile, level 3 and 4 causes represent more specific diseases and injuries [13]. The GBD 2019 estimates the attributable burden for diseases using a framework established for comparative risk assessment (CRA) [12,14].
In this paper, we have presented both all-age and age-standardized rates for prevalence, mortality and overall burden of CKD. Age-standardization was performed using the GBD world population age standard, and non-weighted means were utilized to create a standard population age structure for all countries and territories. The age-standardization method is discussed in greater detail in a previous article from the GBD study [14]. We have reported 95% uncertainty interval (UI) (95% UI) in the article which was estimated taking 1000 draws from the posterior distribution and the 25 th and 975 th -ordered draw constituted 95% uncertainty distribution [12]. Detail methodology of GBD study has been described elsewhere [12,14]. Table 1 shows the number of prevalent cases, all-ages and age-standardized prevalence rate of CKD in Nepal in both sex, male and female separately. In 2019, there were 1, 895,080 prevalent cases (95% UI: 1767115, 2022768) which is an increase from 726,897 prevalent cases (95% UI: 669748, 784674) in 1990. The age-standardized prevalence of CKD increased from 5,979.1 cases per 100,000 population (95% UI: 5539.7, 6400.4) in 1990 to 7,634.7 cases per 100,000 population (95% UI: 7138.8, 8119.4) in 2019. For most of the years, males had a higher agestandardized prevalence than females. However, there is quite an overlap between the UI of age-standardized prevalence of CKD among males and females.

Mortality attributed to CKD
In 2019, CKD due to DM type 2 and CKD due to other and unspecified causes each attributed approximately 0.7% of total deaths. Among other specific CKDs, 0.6% (95% UI: 0.4, 0.8) of total deaths were from CKD due to hypertension, 0.4% (95% UI: 0.3, 0.6) of total deaths were from CKD due to glomerulonephritis, and 0.2% (95% UI: 0.1, 0.3) of total deaths were from CKD due to DM type 1 (Table 4). The burden of CKD as a percentage of total DALYs was 0.5% (95% UI: 0.4, 0.6) in 1990 and increased to 1.8% (95% UI: 1.4, 2.2%) in 2019. The age-standardized DALYs due to CKD were stable from 1990 to 2010 and then increased from 2015 to 2019 for both males and females (Table 5).
The Fig 1 presents the comparison of prevalence rate, death rate, and DALY rate of CKD due to different disease conditions in different age groups between 1990 and 2019. The prevalence rate of CKD due to unspecified cause was highest in age group of 80 years and above with slight rise in the year 2019 compared to 1990. The death rate due to different types of CKDs seem to increase with increasing age. The DALY due CKD due to different diseases has increased in 2019 compared to 1990 for different age group. Fig 2 presents the comparison of age-standardized and all-age YLDs and YLLs in males and females for years from 1990 to 2019. The YLDs and YLLs from CKD seem to have increased for both males and females in the 2019 compared to 1990. Fig 3 shows the major contributing risk factors for CKD. Findings show that kidney dysfunction (5,108 deaths), high systolic blood pressure (2,515 deaths), high fasting plasma glucose (1,733 deaths), high body mass index (1,001 deaths), low temperature (408 deaths) lead exposure (286 deaths), diet high in sodium (238 deaths), and high temperature (4 deaths) were found to be the major risk factors for NCDs.

Prevalence
Globally, as of 2019, there were an estimated 697 million cases of CKD with the increase in all-age prevalence of CKD by 29�3% since 1990 [5,15]. The rise in prevalence could be linked to rise in prevalence of common risk factors of CKD such as obesity, DM and hypertension [16,17]. In context of Nepal too, similar trends are observable where CKD due to DM type 2 and hypertension are the two leading contributors to all-age and age-standardized prevalence of CKD.
The prevalence of CKD identified in this study (all-age prevalence of 6.26%) is comparable to that indicated in some previous studies where authors have analyzed data from a nationally representative survey (6%) in Nepal [10,18]. In one of the other investigations, Dharan, a city in eastern Nepal, had a prevalence of CKD of 10.6% [11]. In a multi-country study (including Nepal), the prevalence of CKD was reported to be 14.3% in the general population with country specific prevalence of 20.1% in Nepal, 29.9% in China, 16.8% in India, 18.0% in Mongolia, 6.3% in Iran, 23.0% in Nigeria, 25.5% in Moldova, and 5.5% in Bolivia [19]. Previous studies in Nepal have demonstrated wide variation in CKD prevalence [10,11,19]. Similar variations were noted in India, where the prevalence of CKD was reported to be 26% by Anand et al. [20], 13.1% by Huda et al. [21] and 12.8% by Fetema et al. [22]. Within country variations in the prevalence rates could be because of methodological differences and the composition of the population represented in the studies. However, all the studies have demonstrated that a significant proportion of the population bear the burden of CKD, thus indicating the need for efforts in primary prevention of disease, early detection, and treatment of CKD.

Mortality and DALYs
Globally, in 2019, CKD was amongst the top 15 causes of death [5]. Meanwhile, the agestandardized death rate from various types of CKDs increased for CKD due to hypertension by 15.33%, CKD from DM type 2 by 24.62%, CKD from glomerulonephritis by 4.86%, and CKD from DM type 1 by 2.35% [5]. Moreover, in context of Nepal, we observed that the agestandardized deaths have increased by about 38% between 1990 and 2019 with increase in specific types of CKDs. Similarly, in 2019, the age-standardized DALYs for CKD caused by DM type 2 increased by 18.18%, CKD caused by glomerulonephritis increased by 1.59%, and CKD caused by hypertension increased by 10.91% globally [5].
Challenges in accessing appropriate treatment [23], relatively high cost of treatment [24], uncontrolled DM type 2 [25], lack of awareness on CKD causing delayed diagnosis [19,24], lack of health insurance to cover the high cost of treatment [26], uncontrolled hypertension [27] could be the reasons contributing to the rising deaths in low resource setting, such as Nepal. One of the study also indicated that population growth and aging are amongst the other factors leading to burden of CKD [28].

Prevention of CKD
As per the World Health Organization, lack of early diagnosis and management of NCDs such as DM and hypertension lead to kidney diseases and therefore needs to be addressed as part of a broader response to prevent major NCDs [29]. For instance, CVDs and CKD have common risk factors and therefore, the preventive majors aimed at reducing the burden of CVDs, a major NCD, will work for CKD prevention. Metabolic risk factors were found to have the highest population attributable fraction (PAF) for CKD in 2019, with the top three being elevated systolic blood pressure, increased fasting plasma glucose, and elevated body mass index [12].
While it is indeed value for money, to address CKD prevention efforts as part of broader NCDs prevention efforts in the country, CKD prevention also requires a targeted strategies. The targeted strategy should involve screening high risk groups such as people with DM and hypertension. Although, screening efforts in low-income settings could be challenging financially as well as logistically [30], the cost incurred is far lower than the cost incurred in treating CKD at end stage and overall burden to the health system. Based on studies from multiple countries, Anand et al. suggested that the two-stage screening strategies (annual dipstick screening for proteinuria followed by confirmatory urine protein to creatinine ratio) could be cost-effective [31]. Other initiatives include educating physicians about the increased risk of CKD and the necessity of testing CKD among patients with cardiometabolic disorders to help with the early detection of the condition [31]. However, for screening and early diagnosis program to be effective, they should be accompanied by lifestyle modifications and appropriate treatment services.
People with CKD should be thought of as having a high risk of CVDs, according to prior studies [19,32]. Therefore, more work is required to promote healthy lives particularly aiming to reduce the contributions of high body mass, high fasting plasma glucose, and high systolic blood pressure in CKD. It is undeniably true that therapies to control hypertension and encourage weight loss are linked to lower chances of CKD development and improved outcomes for people already living with CKD. Apart from early detection of CKD and initiating therapies to improve the quality of life among CKD patients, it is critical to design pertinent strategies and focused interventions to prevent and treat hypertension, diabetes, and obesity which seem to have important role in development and progression of the CKD [12].
Some kidney diseases are treatable, depending on the underlying causes. Although there is no known cure for CKD, there are methods to help regulate signs and symptoms, lessen consequences, and delay the illness's course making early detection of disease an important strategy to improve quality of life [33].

Policy response and financial support
The study showed a high burden of CKD due to DM type 2 in terms of DALYs and deaths in Nepal. With the rising prevalence of DM and other diseases or risk factors linked to CKD, hypertension and glomerulonephritis, the prevalence of CKD is expected to remain as a challenge in years to come. CKD is associated with substantial morbidity, premature mortality and healthcare costs. Taking cognizance of this issue, Government of Nepal started providing support to CKD patients starting with the financial support in 2011 [34]. For patients with renal impairment, the government provides Nepalese Rupees (NRs). 2,00,000 for a kidney transplant, NRs. 1,00,000 as medicine expenses for post-transplant management and free hemodialysis service is available through the selected hospitals in Nepal [35].
In one of the previous study, the cost of providing financial assistance for an estimated 2900 new patients needing dialysis services was projected to be around US$6.7 million on an annual basis, which was roughly 2.1% of the entire health budget [34]. Without a thorough renal registry, it is difficult to estimate the budget needed to support the program in the future. In addition to money, there are other difficulties in providing all CKD patients with access to healthcare. Nepal currently has 1.4 long-term hemodialysis centers, 0.2 peritoneal dialysis centers, 0.1 transplant centers, and 1.7 nephrologists per million people [36]. However, given the rising demand for care and the dispersed distribution of the population, these numbers may not be adequate in the future. As there are just a few hospitals willing to participate in the government program and give their services, there may be a lengthy waiting period [34]. Patients sometimes have significant non-medical costs as well, such as those related to travel, accommodation and food costs while seeking care among others, because hospitals that provide health services are centralized and primarily located in big cities [37]. Possible increasing burden of CKD prevalence and relatively high cost of treatment reiterate the importance of preventive strategies.

Strengths and limitations
The study provides the most comprehensive and current estimates of the burden of CKD in Nepal from 1990 to 2019 using prevalence, death, YLDs, YLLs and DALYs. Our study did, however, have certain shortcomings. This study is based on GBD, therefore, all of the basic drawbacks of GBD methodology also apply particularly relating to low availability of highquality data from the country setting. Despite significant heterogeneity in the risk factors and prevalence of these illnesses, subnational/province-level burden of CKD are not available in this study.

Conclusions
The study reveals a significant and rising burden of CKD in Nepal. In 2019, among the specific types, CKD due to DM type 2 was found to be most prevalent followed by CKD due to hypertension, CKD due to glomerulonephritis and CKD due to DM type 1. Considering the common risk factors of NCDs and their mutual attribution in the burden, country need to implement broad strategies aiming to prevent overall NCDs as well as interventions specific to CKD. Raising awareness, screening, early diagnosis and treatment services should also be prioritized.